Fenofibrate-loaded biodegradable nanoparticles for treating retinal neovascularization

Abstract

Purpose : Fenofibrate is a peroxisome proliferator-activated receptor α (PPARα) agonist and has been shown to have therapeutic effects on diabetic retinopathy (DR). However, the therapeutic effects of fenofibrate through systemic administration are limited due to inefficient drug delivery to the retina. We aimed to explore the long-lasting therapeutic effects of fenofibrate-loaded nanoparticles on both DR and neovascular age-related macular degeneration (AMD).

Methods : Fenofibrate-loaded biodegradable PLGA (34 kDa) nanoparticle (Feno-NP) were prepared, and fully characterized on particle size, surface charge, particle morphology, drug loading, drug release in vitro, and ocular pharmacokinetics in vivo. The efficacy of one single intravitreal injection of Feno-NP on DR and neovascular AMD was investigated using streptozotocin (STZ)-induced diabetic rats, laser-induced choroidal neovascularization (CNV) rats and Vldlr^-/- knockout mice. Therapeutic effects of Feno-NP were evaluated by electroretinogram (ERG), retinal vascular leakage, leukostasis, CNV area and retinal levels of VEGF and ICAM-1.

Results : Feno-NP were spherical with the particle size of ~250 nm (Fig 1A). Feno-NP exhibited a drug content of 6 wt% and a sustained drug release up to 60 days (Fig 1B). One intravitreal injection of Feno-NP in rat eyes maintained sustained fenofibric acid drug level in the eye for more than 60 days (Fig 1C). In STZ rats, one intravitreal Feno-NP (30 µg fenofibrate) ameliorated retinal dysfunctions, reduced retinal vascular leakage, inhibited retinal leukostasis, and downregulated the overexpression of VEGF and ICAM-1 at 8 weeks (Fig 1D). One intravitreal Feno-NP (30 µg fenofibrate for rats, and 9 µg fenofibrate for mice) reduced retinal vascular leakage and formation of CNV in both CNV rats at 2 weeks (Fig 1E) and Vldlr^-/- mice at 4 weeks (Fig 1F). No toxicity of Feno-NP or Blank-NP to retinal structure and function was detected during a 4-week safety study.

Conclusions : A single intravitreal injection of Feno-NP displayed promising therapeutic potential for the treatment of DR and neovascular AMD with prolonged drug release and potentially reduced injection frequency. Feno-NP were made from all Generally Regarded As Safe (GRAS) materials, facilitating the future translational use.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

Fig 1: (A-C) Characterization of Feno-NP; Representative efficacy data of Feno-NP at treating (D) STZ rats, (E) CNV rats, and (F) Vldlr^-/- mice.